EA019957B1 - Preparation for treatment and prophylaxis of endometritis in cows - Google Patents

Abstract

The invention relates to veterinary, gynecology for use in timely expulsion of afterbirth, prophylaxis, treatment and therapy of acute inflammatory processes in uterus after easy and abnormal deliveries, abortions, obstetrics in cows. The preparation comprises an antiseptic as an active substance, a foam-forming base, fillers, a substance having contractile muscle function - oxytocin or propranorol. Polyhexamethylenguanidin with a number of polymeric links n=1-15 or chlorhexidine and also pharmaceutically acceptable salts thereof are selected as the antiseptic.

Description

The invention relates to veterinary medicine, in particular to gynecology, and is intended for the timely separation of the placenta, the prevention and treatment of acute inflammatory processes in the uterus after normal and pathological birth, abortion, obstetrics in cows.

Acute postpartum endometritis is an inflammation of the uterine mucosa. Its clinical manifestations occur in the first 10 days after childbirth and are characterized by abundant secretion of exudate and an enlarged uterus. In most livestock farms, postpartum endometritis is one of the most common pathologies that causes enormous economic damage. Therefore, the quick and effective treatment of endometritis is one of the important economic tasks in the meat and dairy industries (Sidorkin V.A., Yakunin K.A., Klishenko O.A. An integrated approach to the prevention and treatment of endometritis in cows // Zh. Zooindustriya. 2007, No. 6).

Treatment of endometritis involves the solution of several problems: stimulation of the body's defenses; activation of regenerative processes; restoration of contractile function of the body; removal of exudate from the uterus; suppression of pathogenic microflora (Ilyinsky E.V., Nazarov M.V. et al. Guidelines for obstetrics, gynecology and biotechnology of animal reproduction. Textbook. KGAU. Krasnodar, 2002, 381 pp.)

To solve these problems, various medicines are used, which most often contain antibiotics of various classes, nitrofurans and sulfonamides (VI 2275902, publ. 05/10/2006, VI 2333759, publ. 09/20/2008, VI 2306135, publ. 20.09. 2007).

Sometimes antiendometritis drugs contain antiseptics, carbocholine (VI 2085207, publ. 07/27/1997, publ. 2139709, publ. 20.10.1999, publ. 2199323, publ. 02/27/2003, publ. 2272614, publ. 03/27/2006 .).

A complex antimicrobial drug is known for the prevention and treatment of endometritis in cows (VI 2350325, publ. 03/27/2009), containing the antibiotic levomycetin and antiseptics sodium benzoate and potassium sorbate dissolved in propylene glycol.

Known drug for the treatment and prevention of endometritis in cows (VI 2272614, publ. 03/27/2006), which includes the antimicrobial substance dioxin, gelatin, glycerin and distilled water, and food or medical gelatin is used as gelatin, glycerin is used as glycerin. distilled grade I and additionally includes veterinary resorcinol and algalipin in the following ratio of components, g:

dioxidine 0.1-0.3 resorcinol

0.01-0.02 veterinary algalipin

0.9-1.1 food or medical gelatin

1,5-2,0 distilled glycerin grade I

5.0-5.4 distilled water

The disadvantages of the known technical solutions include the use of antibiotics of various classes, which limit the use of meat and dairy products for food purposes, often lead to the emergence of resistance of microorganisms, sometimes to inactivation in biological fluids (Navashin S.M., Fomina I.P. Rational antibiotic therapy , 1982).

Significant disadvantages of dioxidin-containing antimicrobial agents include mutagenic activity, embryotoxicity, and damage to the adrenal cortex. Such toxicological features require the consideration of dioxidine as a reserve preparation.

The closest analogue is a tool for the prevention and treatment of endometritis in cows (Vi 2155046, publ. 08/27/2000), containing an active substance and a foaming base, including polyethylene glycol, citric acid, calcium stearate and surfactant, as an active substance substance contains a complex of iodine with polyvinylpyrrolidone, and the foaming base additionally contains lactose, sodium bicarbonate, ethoxylated fatty alcohols as a surfactant in the following components, wt.%:

Complex of iodine with polyvinylpyrrolidone (active substance antiseptic)

2.1-2.6

10-20

Polyethylene glycol (filler)

30-36

Oxyethylated fatty alcohols (foaming component)

0.6-1.2

Calcium Stearate (Excipient)

Citric acid (foaming component)

Sodium bicarbonate (foaming component)

Lactose (filler)

0.8-1.2

10-14

10-20 rest

- 1 019957

This analogue has the following disadvantages: it does not have a contracting effect on the uterine myometrium, it has a narrowly targeted antimycotic activity; has a fairly high indicator of the service period; idiosyncrasy and irritation from iodine preparations.

The problem to which the invention is directed is the creation of a medicinal product intended for timely separation of the placenta, prevention and therapy of acute inflammatory processes in the uterus of cows in order to reduce the incidence of endometritis.

The technical result of the invention is the timely separation of the placenta and at the same time increase the effectiveness of prevention and treatment of endometritis in cows, reducing the incidence of endometritis. In addition, the invention has a long-term effect, allows you to strengthen and expand the anti-inflammatory, antibacterial and antimycotic effects, eliminates the irritating effect and the addiction of microorganisms to it.

The problem is solved in that the agent for the prophylaxis and treatment of endometritis in cows, including an antiseptic agent as an active substance, a foaming base and excipients, according to the invention, additionally contains a substance with contractile function, a substance containing residues in its molecule is selected as an antiseptic guanidine of the formula (I) (CH ₂ ) b —ΝΗ —ϋΝΗ —ΝΗ- ^ η K (I), where K is (di) hydrochloride, (di) phosphate or (di) gluconate, (amino) benzoate;

n = 1-15, while the components are taken in the following ratio, wt.%:

Antiseptic 0.03 - 0.6

A substance with a contractile function of 1.0-4.0

Foam base 0.5 -30

Fillers rest

Polyhexamethylene guanidinium salts or their pharmaceutically acceptable analogues are selected as an antiseptic.

As a substance having a contractile function, oxytocin or propranolol can be selected.

A combination of polybasic carboxylic acids in an amount of 10-20 wt.%, Basic or acid salts of carbonic acid in an amount of 1030 wt.%, Ethoxylated fatty alcohols as a surfactant in an amount of 0.6-1.2 can be used as a foaming base.

As a filler, the agent contains a combination or one of the following components: di- and polysaccharides, polyhydric alcohols, salts of monobasic saturated carboxylic acids, microcrystalline cellulose and solid polyethylene glycols (PEG).

In particular, at least one of the following components is selected as a filler: lactose monohydrate or anhydrate, starch, carbohydrates or alcohols such as glucose, sucrose, sorbitol, mannitol, xylitol, microcrystalline cellulose or its salts and esters, polymers containing vinylpyrrolidone ; and at least one of the listed glidants: stearic acid, metal salt stearates (magnesium stearate, zinc stearate and calcium stearate), sodium stearyl fumarate, sodium lauryl sulfate, sodium benzoate, solid polyethylene glycols and talc.

The technology for obtaining the claimed composition depends on which antiseptic is chosen for the drug.

Technology 1. For the low molecular weight analogue of chlorhexidine hydrochloride, a conventional technology is used, which consists in simple mixing of the components to a homogeneous mass.

Technology 2. For the low molecular weight analogue of chlorhexidine bigluconate and polyhexamethylene guanidinium salts, the conventional wet granulation technology is used. For this, all components, except the components of the foaming base, are divided into two parts. In one part, basic or acidic salts of carbonic acid are added, in the other - polybasic carboxylic acids. Both parts are separately carried out through wet granulation, including mixing, moistening with a mixture of the active substance dissolved in a 20% solution of isopropyl alcohol to obtain a uniform, uniformly moistened mixture, granulation, drying. Then both granular parts are mixed and sieved through a sieve.

Obtained by technology 1 or 2, the mass is transferred to the loading hopper of the tablet press. Obtained tablets of elongated shape (length 3.8 cm, width 2.2 cm, height 0.85 cm).

Finished tablets are packaged in a double foil blister, which is labeled with the batch number, month and expiration date.

The tablets have high storage stability and can be manufactured in the factory as a finished dosage form.

Examples of specific performance are given in table. 1, which indicates the ratio of the components in the preparation per tablet (10 g) in different formulations.

- 2 019957

Table 1

Name of components Content of components in prep eate. mass% No. 1 Number 2 No. 3 Composition 1 Chlorhexidine hydrochloride 0,03 0.3 0.6 Propranolol 1,0 2.0 4.0 Kremafor A 25 0.3 0.6 0.6 Cremaphore A 6 0.3 0.3 0.6 Magnesium stearate 0.5 0.9 1,2 Lemon acid 10 fifteen twenty Bicarbonate of soda 5 8 fifteen Sodium carbonate 5 7 fifteen PEG 1500 0.5 3 5 PEG 4000 0.5 2 5 Mannitol 10 fifteen thirty Lactose rest Composition 2 Chlorhexidine bigluconate 0,03 0.3 0.6 Oxytocin 1,0 2.0 4.0 Kremafor A 25 0.3 0.6 0.6 Cremaphore A 6 0.3 0.3 0.6 Magnesium stearate 0.5 0.9 1,2 Lemon acid 10 fifteen twenty Bicarbonate of soda 5 8 fifteen Sodium carbonate 5 7 fifteen PEG 1500 0.5 3 5 PEG 4000 0.5 2 5 lactose rest Composition 3 Polyhexamethylene guanidine dihydrochloride 0,03 0.3 0.6 Propranolol 1,0 2.0 4.0 Kremafor A 25 0.3 0.6 0.6 Cremaphore A 6 0.3 0.3 0.6 Magnesium stearate 0.5 0.9 1,2 Lemon acid 10 fifteen twenty Bicarbonate of soda 10 fifteen thirty PEG 4000 1,0 5 10 lactose rest Composition 4 Polyhexamethylene guanidine phosphate 0,03 0.3 0.6 Oxytocin 1,0 2.0 4.0 Kremafor A 25 0.3 0.6 0.6 Cremaphore A 6 0.3 0.3 0.6 Magnesium stearate 0.5 0.9 1,2 Lemon acid 10 fifteen twenty Sodium carbonate 10 fifteen thirty PEG 1500 1,0 5 10 lactose rest

The drug is administered intrauterine in the following doses: to separate the afterbirth - 2 tablets, once; for the prevention of acute endometritis - 2 tablets, 2-4 hours after separation of the placenta once; for the treatment of acute endometritis - 2 tablets twice with an interval of 24 hours (in special cases, administration is continued until recovery); for the treatment of endometritis caused by microorganisms (fungi and protozoa) - 2 tablets with an interval of 12 hours (morning and evening), for 2-3 days in combination with etiotropic drugs.

Tests of the claimed funds in animals were carried out in comparison with iodopene (tab. 2-7).

In the table. 2 presents the results of tests of the preventive effectiveness of the drug in the separation of the placenta.

table 2

No. Indicators R groups 1 control "Iodopen" 2 experimental (LF No. 1) 3 experimental (LF No. 3) one Quantity Goal 17 17 fifteen 2 Dose 2 tablets, intrauterine device, once 2 tablets, intrauterine device, once 3 The time of separation of the placenta, hour 5-7 3-4

- 3 019957

From the data obtained it follows that in the experimental groups, where the animals were used LF No. 1 and 3 of the claimed funds, the separation of the placenta occurs 1.7 times faster than in the control group.

In order to determine the effectiveness of the prophylaxis of acute endometritis of cows by the claimed agent, 3 groups of animals were formed on the basis of analogues. The animals of the control group were injected intrauterine drug Iodopen. Cows of the second and third experimental groups were injected with the intrauterine device according to the invention in 2 tablets, 2-4 hours after separation of the placenta once. As a result of prophylactic treatment of cows after calving with the claimed means, a good food reflex, the absence of pathological discharge from the vagina and the normal state of the mucous membranes were noted in most animals.

During a 5-day observation, 4 cows of the control group showed an increase in body temperature by 1-3 ° C, fever, decreased appetite, and depression. In cows, turbid mucous discharges from the vagina periodically, gluing of the remnants of the secretions under the tail, which indicates the development of postpartum endometritis, were periodically observed in cows.

In the table. 3 shows the results of a blood test in cows of the control and experimental groups. Table 3

Indicators Groups 1-control "Iodopen" 2-experienced (LF№1) 3-experienced (LF No. 3) Hemoglobin, g / l 92.4 + 0.7 98.3 + 1.1 112.5 + 1.6 Red blood cells 10 ¹² / l 5.74 + 1.0 6.01 + 0.4 7.94 + 0.3 White blood cells 10 ⁹ / l 6.93 + 0.9 6.41 + 0.5 6.23 + 0.8 Total protein, g / l 62.6 + 3.4 66.8 + 3.4 64.9 + 3.1 Total calcium, mmol / l 2.42 + 0.4 2.37 + 0.13 2.35 + 0.17 Norg. phosphorus, mmol / l 2.36 + 0.2 2.21 + 0.16 2.19 + 0.14 Glucose mol / l 2.51 + 0.1 2.31 + 0.12 2.42 + 0.16 Lipids, mg% 283 + 13 274 + 13 279 + 17 Alkaline reserve, mg% 53.2 + 2.6 51.3 + 2.3 52.8 + 3.7

Analysis of hematological data showed that animals subjected to prophylactic treatment with the drug have more optimal blood counts. This primarily relates to the concentration of red blood cells and hemoglobin in the blood of cows, which are 6.4 and 21.7% higher than those in the control, respectively. The number of leukocytes is 7.5-10% less in cows of the experimental groups. Other indicators also testify in favor of experimental groups.

Hematological parameters confirm clinical studies and allow us to conclude that the claimed drug has a higher prophylactic efficacy of postpartum acute endometritis in cows than the drug Iodopen.

In the table. 4 presents the results of tests of the therapeutic effectiveness of the drug in the treatment of acute endometritis.

: Indicators

Number of animals, goal Recovery time, days Recovered, goal? Therapeutic efficacy, Service period, days ΐ Fertilized at the first! insemination goal

I Toxic effect, goal

Table 4

| Claimed drug - “Yodopen” ί LF№3 LF№1 ; 23 21 . 22 (6.1 + 0.62 7.3 + 0.54 9.4 + 0.96 '23 twenty eighteen ί 100 95.2 81.8 ί 49.3 + 7.88 50.6 + 4.21 54.3 + 2.7 ί 21 nineteen 17 ! θ 0  0

The therapeutic efficacy of the claimed agent in the treatment of cows with postpartum acute endometritis was 100% when administered with LF No. 3, 95.2% with LF No. 1, which is 4.8 and 18.2% higher than as a result of the use of Iodopen .

The service period, on average per animal, in experimental group No. 1 was 49.3 + 7.88, in group No. 2 - 50.6 + 4.21, which was 5.0 less compared to cows in the control group and 3.7 days. A shorter service period confirms the therapeutic efficacy of the claimed drug.

Hematological parameters of a blood test were performed on the 7th day of the experiment (table. 5).

- 4 019957

Table 5

Indicators Groups 1 (control) 2 (experienced) 3 (experienced) Hemoglobin, g / l 91.7 ± 1.2 10 "D ± 1,3 119.3 ± 1.1 Red blood cells 10 ¹² / L. 5.48 ± 0.6 6.18 ± 0.3 8.77 ± 0.2 White blood cells 10 ⁹ / l 7.97 ± 0.7 6.72 ± 0.4 5.58 ± 0.6 Total protein, g / l 67.1 ± 3.9 83.5 ± 3.4 87.6 ± 3.5 Total calcium, mmol / l 2.12 ± 0.15 2.64 ± 0.13 2.36 ± 0.11 Norg. phosphorus, mmol / l 2.37 ± 0.10 2.26 ± 0.16 2.31 ± 0.12 Glucose mol / l 2.65 ± 0.15 2.43 ± 0.13 2.58 ± 0.18 Lipids, mg% 285 ± 19 276 ± 12 289 ± 16 Alkaline reserve, mg% 54.6 ± 2.3 48.3 ± 3.3 51.7 ± 3.9

The content of red blood cells and hemoglobin in the cows of the experimental groups having postpartum complications is higher than in animals in the group with the drug Iodopen. The content of leukocytes characterizing the presence of inflammatory processes in the body turned out to be lower by 17.9-30%, respectively, in animals to which the claimed preparation was used for therapy. Other biochemical parameters also indicate intense metabolism and the development of postpartum pathology in cows of the control group.

Thus, it follows from the results obtained that the therapeutic efficacy of the claimed agent in acute postpartum endometritis is higher than in the group with the drug Iodopen.

It is known that the course of endometritis can be complicated by such pathogenic microflora as fungi, including Saiya Acretdic and others; bacteria, among which §1ter1ossoss8 roudepec, 81aryu1ossoss8 aiteik, E.coN, Ptolei8 ui1d8, Rkeiotopak aetidoka prevail. Therefore, prior to using the claimed drug, the animals were tested for antimicrobial activity, in comparison with the already known drug Iodopen (table. 6).

Table 6

Microorganism culture Yodopen Claimed drug LF№1 LF№3 81 arb + 4- 4- 81ger1ossoss rudepez 4 + 4- E. soi 4- + 4- Рgo1еиз уиЦапз + + 4- Rzeyotopaz aegidtosis + + + Сап Ш <1а аПлсапз - + 4* Asypotuzez ruodepez - + + Azregd Schiz £ total 1 out - 4- 4- + antimicrobial and antifungal activity of the drug - lack of sensitivity to the drug

The data obtained (table. 6) indicate a wider spectrum of antimicrobial action of the claimed drug than the drug Iodopen.

To assess therapeutic efficacy in catarrhal-purulent endometritis, the studied drugs were used in combination with etiotropic drugs. The treatment results are presented in table. 7.

Table 7

Indicators Claimed drug Yodopen LF№3 LF№1 Number of animals, goal 28 thirty thirty Recovery time, days 10.5 ± 0.58 9.7 ± 0.43 14.4 ± 0.81 The number of drug injections 5.09 ± 0.48 3.72 ± 0.34 2.0 ± 0.15 Recover, goal 26 27 21 Therapeutic efficacy,% 92.8 90 70 Service period, days 73.6 ± 5.32 82.3 ± 5.71 89.7 ± 6.09 Fertilized at the first insemination,% 76.3 72.8 53.3 Toxic effect, goal 0 0 0

- 5 019957

As can be seen from the table, the use of the claimed funds for endometritis not only reduces the recovery period of animals, but also reduces the service period by 16.1 ± 2.37 and 7.4 ± 3.19, respectively, compared with animals in the group with the drug Iodopen.

The therapeutic efficacy is also higher in groups with the claimed drug by 22.8% (LF No. 1) and 20% (LF No. 2) than in cows in the group with the drug Iodopen.

The percentage of fertilization in the groups with the claimed drug was 76.3 and 72.8%, which is 23 and 19.5% higher than in animals in the group with the base drug.

Thus, the drug for intrauterine administration is an effective tool in the prevention of separation of the placenta, acute postpartum endometritis, treatment of acute endometritis and endometritis caused by microorganisms in cows (including catarrhal-purulent endometritis), possessing, along with antimicrobial action, high anti-inflammatory activity, as evidenced by a simultaneous reduction in treatment time and the amount of drug used.

Claims (5)

CLAIM 1. An agent for the prevention and treatment of endometritis in cows, including an antiseptic agent as an active substance, a foaming base and fillers, characterized in that it additionally contains a substance with contractile function, oxytocin or propranorol, polyhexamethylene guanidine with the number of polymer units selected as an antiseptic n = 1-15 or chlorhexidine, as well as their pharmaceutically acceptable salts, with the components taken in the following ratio, wt.%: Antiseptic 0.03 - 0.6 Substance possessing a contractile function 1.0 - 4.0 Foaming base 0.5 - 30 Fillers rest 2. The tool according to claim 1, characterized in that organic salts, such as polyhexamethylene guanidinium bigluconate, or polyhexamethylene guanidinium benzoate, or polyhexamethylene guanidinium aminobenzoate, are selected as pharmaceutically acceptable salts of polyhexamethylene guanidinium. 3. The tool according to claim 1, characterized in that inorganic salts such as polyhexamethylene guanidinium dihydrochloride, polyhexamethylene guanidinium phosphate are selected as pharmaceutically acceptable salts of polyhexamethylene guanidinium. 4. The tool according to claim 2, characterized in that either chlorhexidine hydrochloride or chlorhexidine bigluconate is selected as the pharmaceutically acceptable salts of chlorhexidine. 5. The tool according to claim 1, characterized in that at least one of the following components is selected as a filler: lactose monohydrate or anhydrate, starch, carbohydrates or alcohols, such as glucose, sucrose, sorbitol, mannitol, xylitol, microcrystalline cellulose or its salts and esters, polymers containing vinylpyrrolidone; and at least one of the listed glidants: stearic acid, stearates of metal salts selected from magnesium, zinc and calcium salts, sodium stearyl fumarate, sodium lauryl sulfate, sodium benzoate, solid polyethylene glycols and talc. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2